JP4231217B2 - Ceramic precursor, heat-treated body thereof, and method for producing porous calcium phosphate ceramic sintered body using them - Google Patents

Description

[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a precursor of porous calcium phosphate ceramic sintered body useful for carriers used for culturing cells and biological tissues, artificial biomaterials having biocompatibility such as for bone filling, and ceramic sintering using the same. The present invention relates to a method for manufacturing a body.
[0002]
[Prior art]
Calcium phosphate ceramics such as hydroxyapatite are excellent in biocompatibility, and are used as carriers for culturing cells and living tissues, and as biomaterials such as artificial tooth roots and bone reinforcing materials. From the viewpoint of mechanical strength, the calcium phosphate ceramics are better as they are denser, but from the viewpoint of biocompatibility, the more porous, that is, the higher the porosity is better. For this reason, various methods such as a foaming agent addition method, a thermally decomposable resin bead addition method, a sponge resin impregnation method, and a water-soluble polymer gelation method have been proposed as methods for producing porous calcium phosphate ceramics. Yes.
[0003]
However, since the dried body (ceramic precursor) before sintering the porous calcium phosphate ceramics has a lower strength and tends to be brittle as the porosity increases, it needs to be handled carefully and is difficult to process. On the other hand, if the binder concentration is increased for the purpose of improving the handleability and workability of the dried body before sintering, problems such as difficulty in obtaining the desired high porosity occur.
[0004]
[Problems to be solved by the invention]
Accordingly, an object of the present invention is to provide a ceramic precursor excellent in handleability and workability and a method for producing a porous calcium phosphate ceramic sintered body using the same.
[0005]
[Means for solving the problems]
As a result of diligent research in view of the above object, the present inventor added a thermoplastic resin to the ceramic precursor, and fused the resin component at 200 to 300 ° C. to strengthen the precursor, thereby handling and processing. As a result, the inventors have found that the porous calcium phosphate-based ceramic sintered body can be easily manufactured, and have arrived at the present invention.
[0006]
That is, the ceramic precursor of the present invention is characterized by containing a thermoplastic resin.
[0007]
The ceramic precursor of the present invention contains a thermoplastic resin in an amount of 1% by weight or more of the whole precursor, and the thermoplastic resin has a spherical shape with an average particle diameter of 10 μm or less . The heat treatment of the ceramic precursor of the present invention is formed by fusing the thermoplastic resin by heating the ceramic precursor at 200 to 300 [° C..
[0008]
The method for producing a porous calcium phosphate ceramic sintered body having a porosity of 75 to 95% according to the present invention includes: (1) a calcium phosphate ceramic powder, a water-soluble polymer compound, a nonionic surfactant, Making a slurry containing a plastic resin, (2) foaming the slurry by vigorously stirring, (3) gelling, (4) fusing the thermoplastic resin at 200-300 ° C. after drying, (5) It is characterized by sintering.
[0009]
The calcium phosphate ceramic powder is preferably secondary particles having an average particle size of 0.5 to 80 μm made of primary particles of calcium phosphate ceramic having an average length in the major axis direction of 100 nm or less.
[0010]
The water-soluble polymer compound is preferably a cellulose derivative, and the nonionic surfactant is preferably a fatty acid alkanolamide surfactant.
[0011]
1 to 10 parts by weight of water-soluble polymer compound and 1 to 10 parts by weight of nonionic surfactant are added to 100 parts by weight of calcium phosphate ceramic powder, and 1% by weight or more of thermoplastic resin is added. It is preferable to do this.
[0012]
The total concentration of calcium phosphate ceramic powder + water-soluble polymer compound + nonionic surfactant + thermoplastic resin in the slurry is preferably 20 to 50% by weight.
[0013]
In the slurry agitation foaming treatment, it is preferable that the temperature during the treatment is maintained at 5 to 20 ° C., and the agitation is performed strongly while blowing gas into the slurry with an agitation force of 50 W / L or more.
[0014]
The nonionic surfactant preferably contains neither metal ions nor sulfate groups, and the calcium phosphate ceramic is preferably hydroxyapatite.
[0015]
DETAILED DESCRIPTION OF THE INVENTION
[1] Ceramic precursor A ceramic precursor means a dried body before ceramic sintering produced in the process of manufacturing a porous calcium phosphate ceramic sintered body, specifically, calcium phosphate ceramic powder, water-soluble It is a dried product of a gel prepared from a polymer compound, a nonionic surfactant and a thermoplastic resin. Each component will be described below.
[0016]
(1) Calcium phosphate ceramic powder The calcium phosphate ceramic powder used in the present invention is preferably a hydroxyapatite powder [Ca ₁₀ (PO ₄ ) ₆ · (OH) ₂ ]. The hydroxyapatite powder is preferably secondary particles having an average particle size of 0.5 to 80 μm composed of primary particles having an average length in the major axis direction of 100 nm or less. In order to improve the stirring property of the slurry and the moldability of the ceramic precursor, the hydroxyapatite powder is preferably spherical particles.
[0017]
(2) Water-soluble polymer compound The water-soluble polymer compound used in the present invention is such that it gels by subjecting the water-soluble or water dispersion to a means such as heating. Here, the water-soluble or aqueous dispersion includes all of an aqueous solution, a colloidal solution, an emulsion, and a suspension. Examples of such water-soluble polymer compounds include cellulose derivatives such as methylcellulose and carboxymethylcellulose, polysaccharides such as curdlan, synthetic polymers such as polyvinyl alcohol, polyacrylic acid, polyacrylamide, and polyvinylpyrrolidone. Methyl cellulose is preferred. In the case of polyvinyl alcohol, it can be gelled by adding boric acid or borax.
[0018]
(3) Nonionic surfactant A nonionic surfactant is preferably used as a surfactant having the property of forming a large number of fine bubbles by vigorous stirring and not causing the bubbles to disappear in the heating step for gelation. It is done. In addition, since porous calcium phosphate ceramics are used semi-permanently in the body as a biomaterial, the added nonionic surfactants are not only completely burned away by sintering, but also remain after sintering. The metal ions such as those that do not contain sulfate groups are preferred.
[0019]
Examples of such nonionic surfactants include fatty acid alkanolamides, polyoxyethylene alkyl ether carboxylates, polyoxyethylene alkyl ethers (for example, polyoxyethylene octyl phenyl ether) and the like. Of these, fatty acid alkanolamide surfactants (for example, N, N-dimethyldodecylamine oxide) are preferred from the viewpoint of foaming properties in the presence of hydroxyapatite.
[0020]
(4) Thermoplastic resin The ceramic precursor of the present invention is characterized by containing a thermoplastic resin. The thermoplastic resin is preferably a substance that melts at 200 ° C. or higher and completely decomposes at 1000 ° C. or higher because the thermoplastic resin increases the mechanical strength of the ceramic precursor by heat fusion and is completely burned off by sintering. As such a thermoplastic resin, polyethylene, polypropylene, polystyrene, polyvinyl chloride, polyamide (nylon 6, nylon 6,6, nylon 11, nylon 12, etc.), acrylic resin (polyacrylate ester, polymethacrylate ester, etc.) Etc. Among these, polystyrene or an acrylic resin excellent in processability by itself is preferable.
[0021]
The content of the thermoplastic resin is preferably 1% by weight or more of the whole precursor, more preferably 1 to 5% by weight. If it is less than 1% by weight, sufficient mechanical strength cannot be imparted to the ceramic precursor, and if it exceeds 5% by weight, an increase in mechanical strength commensurate with it cannot be obtained. The shape of the thermoplastic resin is preferably spherical in order to improve the moldability of the precursor, and the average particle size is preferably 10 μm or less in order to be uniformly dispersed in the precursor.
[0022]
[2] Porous calcium phosphate ceramics sintered body
(1) Composition The porous calcium phosphate ceramic sintered body produced by the production method of the present invention preferably has a Ca / P weight ratio of 1.6 to 1.7. If the weight ratio of Ca / P after sintering is less than 1.6, it becomes a mixed phase with tricalcium phosphate [Ca ₃ (PO ₄ ) ₂ ], and if it exceeds 1.7, it becomes a mixed phase with calcium oxide (CaO). It becomes. A preferred example of the porous calcium phosphate ceramic sintered body to which the present invention is applied is a porous hydroxyapatite sintered body [Ca ₁₀ (PO ₄ ) _6. (OH) ₂ ].
[0023]
(2) Porosity The porous calcium phosphate ceramic sintered body produced by the production method of the present invention preferably has a porosity of 75 to 95%. Such a porous calcium phosphate ceramic sintered body having a high porosity has an extremely high biocompatibility. When the porosity is 75% or less, the biocompatibility is not sufficient, and when it exceeds 95%, the mechanical strength is insufficient and the processability and the handleability are poor.
[0024]
The average pore diameter of the porous calcium phosphate ceramic sintered body is preferably 5 to 1500 μm. If the average pore diameter is less than 5 μm, it becomes difficult to form cells or blood vessels, and if it exceeds 1500 μm, it is difficult to obtain a stable mechanical strength, and there is a large variation in processability and handleability for each product lot. Too much. Since the pore diameter in the porous calcium phosphate ceramic sintered body is preferably uniform, most (80% or more) of the pore diameters are preferably in the range of 50 to 500 μm.
[0025]
[3] Method for Producing Porous Calcium Phosphate Ceramic Sintered Body The production method of the present invention will be described below by taking the case of a porous hydroxyapatite sintered body as an example. Can also be applied.
[0026]
(1) Preparation of slurry A slurry containing a hydroxyapatite powder, a water-soluble polymer compound, a nonionic surfactant and a thermoplastic resin is prepared.
[0027]
(a) The calcined hydroxyapatite powder is preferably subjected to a calcining treatment in order to obtain a powder strength that can withstand strong stirring. The calcination treatment consists of heat treating the powder at a temperature of 700 to 850 ° C. for 4 to 10 hours. If the calcining temperature is less than 700 ° C, sufficient improvement in the strength of the hydroxyapatite powder cannot be achieved, and if it exceeds 850 ° C, sintering starts, so that not only grain growth occurs, but also after calcining Grinding is required.
[0028]
(b) Mixing ratio and concentration In the slurry, it is preferable to mix 100 parts by weight of hydroxyapatite powder, 1 to 10 parts by weight of a water-soluble polymer compound, and 1 to 10 parts by weight of a nonionic surfactant. Furthermore, it is preferable to add a thermoplastic resin in an amount of 1% by weight or more based on the total solid content. If the amount of the hydroxyapatite powder is too small, it takes too much time to dry, and if too much, the viscosity of the slurry is too high and foaming is difficult. A more preferable amount of the water-soluble polymer compound is 1 to 5 parts by weight. Further, if the blending amount of the nonionic surfactant is less than 1 part by weight, foaming is difficult, and even if it exceeds 10 parts by weight, the effect corresponding to that cannot be improved. The more preferable amount of the nonionic surfactant is 1 to 5 parts by weight. Moreover, the more preferable addition amount of a thermoplastic resin is 1 to 5 weight% of the whole solid content.
[0029]
The total concentration of hydroxyapatite powder + water-soluble polymer compound + nonionic surfactant + thermoplastic resin in the slurry is preferably 20 to 50% by weight. When the total concentration of these components is less than 20% by weight, it takes too much time for drying after gelation, and the gel is crushed after drying, so that the porous shape cannot be maintained. On the other hand, when the total concentration is more than 50% by weight, the viscosity of the slurry is too high and stirring and foaming are difficult. A more preferred total concentration is 25 to 40% by weight.
[0030]
(2) Foaming When the slurry having the above composition is vigorously stirred, the slurry entrains and foams. The stirring power is preferably 50 W / L or more. When the stirring power is less than 50 W / L, foaming is insufficient and porous hydroxyapatite having a desired porosity cannot be obtained. The stirring force is determined by [maximum output of stirrer (W) / amount of aqueous solution (L)] × (actual rotational speed / maximum rotational speed). The output of the stirrer increases in order to maintain the rotation speed when the viscosity of the slurry increases, but in the case of the present invention in which foaming is performed at a high porosity, the slurry viscosity does not substantially change from the viscosity at the time of charging. Therefore, the effect of viscosity is virtually negligible.
[0031]
As an apparatus capable of obtaining such a stirring force, an impeller type homogenizer may be mentioned. Impeller type homogenizers are originally designed so that foaming does not occur. However, if the stirring condition is 50 W / L or more, significant foaming is possible. In addition, it is preferable to use a stirring device having a structure in which the stirring blade is formed in a disk shape, a saw blade-like unevenness is provided on the outer periphery of the disk, and a baffle plate is provided on the inner wall of the stirring container. Examples of the impeller homogenizer having such a structure include PH91, PA92, HF93, FH94P, PD96, and HM10 manufactured by SMT Co., Ltd. Further, in order to further promote the bubbles, it is preferable to inject an inert gas such as air, nitrogen, or argon into the stirring slurry.
[0032]
The stirring time depends on the stirring force, but generally it may be about 1 to 30 minutes. In order to make the bubbles fine and uniform and stabilize, it is preferable to foam at a relatively low temperature, specifically about 0 to 25 ° C., particularly preferably 5 to 20 ° C. .
[0033]
It is preferable to cast the foamed slurry into a mold in which a flexible water-resistant film is stretched on the inner wall. As a result, the film peels off from the mold as the ceramic shrinks during drying, so that the ceramic does not collapse on the surface in contact with the mold and does not crack inside, and an excellent dry body can be obtained.
[0034]
(3) When a slurry sufficiently foamed by gelation stirring is heated to 80 ° C. or higher and lower than 100 ° C., it is gelled by the action of a water-soluble polymer compound such as methyl cellulose. When the heating temperature is less than 80 ° C., gelation is insufficient, and when it is 100 ° C. or more, the water boils and the gel structure is destroyed.
[0035]
(4) Drying of the dried gel is preferably carried out by keeping it at a high temperature (for example, not lower than 80 ° C. and lower than 100 ° C.) such that water does not boil. By drying the gel, the ceramic precursor shrinks substantially isotropically to obtain a fine and uniform spherical macropore.
[0036]
(5) Heat treatment The obtained ceramic precursor is heat treated. Since the thermoplastic resin melts at 200 ° C. or higher, it is preferably performed by heating at a temperature of 200 to 300 ° C. for 0.5 to 3 hours. After the thermoplastic resin contained in the precursor is melted by the heat treatment, it is solidified by cooling and fused to the gel. The fused thermoplastic resin firmly holds the structure of the ceramic precursor and prevents collapse and the like.
[0037]
(6) The ceramic precursor heat-treated by adding a processed thermoplastic resin has improved mechanical strength as compared with the case where the ceramic precursor is fixed only with a binder. Therefore, it is excellent in handleability and workability, and can be easily performed while preventing breakage or the like even if it is cut as it is without drying.
[0038]
(7) Sinter the sintered ceramic precursor at 1000-1250 ° C. for 2-10 hours. When the sintering temperature is less than 1000 ° C., porous hydroxyapatite having sufficient strength cannot be obtained, and when it exceeds 1250 ° C., hydroxyapatite is decomposed into tricalcium phosphate and calcium oxide. What is necessary is just to set sintering time suitably according to sintering temperature. The degreasing treatment (decomposition and removal of the water-soluble polymer compound, nonionic surfactant and thermoplastic resin) can be performed by gradually raising the temperature until reaching the sintering temperature. The water-soluble polymer compound and the nonionic surfactant can be removed by heating to 300 to 900 ° C., and the thermoplastic resin can be removed by heating to 1000 ° C. or higher. For example, the temperature is raised from room temperature to about 600 ° C. at a temperature raising rate of about 10 to 100 ° C./hour, and then raised to the sintering temperature at a temperature raising rate of 50 to 200 ° C./hour and held at this temperature. Is preferred. Slowly cool after completion of sintering.
[0039]
【Example】
The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.
[0040]
Example 1
120 parts by weight of hydroxyapatite spherical powder (average particle size: 10 μm) composed of elongated primary particles (average diameter: major axis 78 nm, minor axis 23 nm), methylcellulose (manufactured by Wako Pure Chemical Industries, Ltd., 2% by weight) 320 parts by weight of a 1% by weight aqueous solution of an aqueous solution measured at 20 ° C. (4000 cps) and 10 weights of a fatty acid alkanolamide surfactant (N, N-dimethyldodecylamine oxide, “AROMOX”, manufactured by Lion Corporation) Part (solid content basis) and 3 parts by weight of polymethyl methacrylate resin (average particle size: 3 μm) were blended. The obtained slurry was put into a homogenizer (manufactured by SMT Co., Ltd., PA92). While maintaining the slurry temperature at 8 ° C., the slurry was vigorously stirred for 5 minutes with a stirring force of 60 W / L (actual output during stirring) to cause foaming.
[0041]
The foam-containing slurry was poured into a mold and heated to 83 ° C. for 2 hours to cause gelation. The obtained gel was completely dried by maintaining at 83 ° C. to obtain a ceramic precursor.
[0042]
The obtained ceramic precursor was heat-treated at 200 ° C. for 1 hour with a dryer to melt the resin component.
[0043]
After processing the ceramic precursor with the resin component fused into a 30mm x 15mm x 10mm shape, the temperature is raised from room temperature to 600 ° C at a heating rate of 50 ° C / hour in the atmosphere, and then 100 ° C / hour The temperature was raised to 1200 ° C at a temperature increase rate of 4 ° C, calcined at this temperature for 4 hours, cooled to 600 ° C at a temperature decrease rate of 50 ° C / hour, held at this temperature for 4 hours, and then the temperature decrease rate of 100 ° C / hour. At room temperature. A porous hydroxyapatite sintered body was produced by this sintering process. The porosity of the obtained sintered body was 85%.
[0044]
Comparative Example 1
120 parts by weight of the same hydroxyapatite powder as in Example 1, 320 parts by weight of a 1% by weight aqueous solution of methylcellulose, a fatty acid alkanolamide surfactant (N, N-dimethyldodecylamine oxide, “ARMOX”, manufactured by Lion Corporation) ) 10 parts by weight (based on solid content). The obtained slurry was put into a homogenizer (manufactured by SMT Co., Ltd., PA92). While maintaining the slurry temperature at 8 ° C., the slurry was vigorously stirred for 5 minutes with a stirring force of 60 W / L (actual output during stirring) to cause foaming.
[0045]
The foam-containing slurry was poured into a mold and heated to 83 ° C. for 2 hours to cause gelation. The obtained gel was completely dried by maintaining at 83 ° C. to obtain a ceramic precursor.
[0046]
The obtained ceramic precursor was processed into a shape of 30 mm × 15 mm × 10 mm. Next, the temperature was raised and fired in the same manner as in Example 1 to produce a porous hydroxyapatite sintered body. Since the ceramic precursor by this method is easily broken during processing, careful operation is required. The porosity of the obtained sintered body was 85%.
[0047]
【The invention's effect】
As described above, since the ceramic precursor of the present invention contains a thermoplastic resin, the precursor is strengthened by fusing it, and has excellent handleability and workability. Therefore, it is possible to easily produce a porous calcium phosphate ceramic sintered body without affecting the porosity after sintering.

Claims (13)

A porous calcium phosphate ceramic sintered body precursor having a porosity of 75 to 95%, containing a thermoplastic resin in an amount of 1% by weight or more of the whole ceramic precursor, and the thermoplastic resin having an average particle diameter of 10 μm A ceramic precursor characterized by the following spherical shape. Porosity a heat treatment of the precursor 75 to 95% of porous calcium phosphate-based ceramic sintered body, containing an average particle size of 1 wt% or more of the total of the thermoplastic resin of the following spherical 10 mu m A heat treatment body for a ceramic precursor obtained by heat-treating the precursor at 200 to 300 ° C. to fuse the thermoplastic resin. A method for producing a porous calcium phosphate ceramic sintered body having a porosity of 75 to 95%, comprising: (1) a calcium phosphate ceramic powder, a water-soluble polymer compound, a nonionic surfactant, and thermoplasticity (2) foaming the slurry by vigorously stirring, (3) gelling, and (4) fusing the thermoplastic resin at 200 to 300 ° C. after drying. (5) A method characterized by sintering. 4. The method for producing a porous sintered calcium phosphate ceramic according to claim 3, wherein the calcium phosphate ceramic powder has an average particle size of 0.5˜ A method characterized by being secondary particles of 80 μm. The method for producing a porous calcium phosphate ceramic sintered body according to claim 3 or 4, wherein the water-soluble polymer compound is a cellulose derivative. 6. The method for producing a porous calcium phosphate ceramic sintered body according to any one of claims 3 to 5, wherein the nonionic surfactant is a fatty acid alkanolamide surfactant. The method for producing a porous calcium phosphate-based ceramic sintered body according to any one of claims 3 to 6, wherein 1 to 10 parts by weight of the water-soluble polymer compound is added to 100 parts by weight of the calcium phosphate-based ceramic powder. A method comprising blending 1 to 10 parts by weight of a nonionic surfactant and further adding 1% by weight or more of the thermoplastic resin. In the manufacturing method of the porous calcium phosphate ceramic sintered body according to any one of claims 3 to 7, the calcium phosphate ceramic powder in the slurry + the water-soluble polymer compound + the nonionic surfactant + The total concentration of the thermoplastic resin is 20 to 50% by weight. The method for producing a porous calcium phosphate ceramic sintered body according to any one of claims 3 to 8, wherein the slurry is stirred with a stirring force of 50 W / L or more. The method for producing a porous calcium phosphate ceramic sintered body according to any one of claims 3 to 9, wherein the temperature during the stirring and foaming treatment of the slurry is maintained at 5 to 20 ° C. The method for producing a porous calcium phosphate ceramic sintered body according to any one of claims 3 to 10, wherein the nonionic surfactant contains neither metal ions nor sulfate groups. The method for producing a porous calcium phosphate ceramic sintered body according to any one of claims 3 to 11, wherein the slurry is vigorously stirred while blowing gas into the slurry. 13. The method for producing a porous calcium phosphate ceramic sintered body according to any one of claims 3 to 12, wherein the calcium phosphate ceramic is hydroxyapatite.